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      Pathways of calcium regulation, electron transport, and mitochondrial protein translation are molecular signatures of susceptibility to recurrent exertional rhabdomyolysis in Thoroughbred racehorses

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          Abstract

          Recurrent exertional rhabdomyolysis (RER) is a chronic muscle disorder of unknown etiology in racehorses. A potential role of intramuscular calcium (Ca 2+) dysregulation in RER has led to the use of dantrolene to prevent episodes of rhabdomyolysis. We examined differentially expressed proteins (DEP) and gene transcripts (DEG) in gluteal muscle of Thoroughbred race-trained mares after exercise among three groups of 5 horses each; 1) horses susceptible to, but not currently experiencing rhabdomyolysis, 2) healthy horses with no history of RER (control), 3) RER-susceptible horses treated with dantrolene pre-exercise (RER-D). Tandem mass tag LC/MS/MS quantitative proteomics and RNA-seq analysis (FDR <0.05) was followed by gene ontology (GO) and semantic similarity of enrichment terms. Of the 375 proteins expressed, 125 were DEP in RER-susceptible versus control, with 52 ↑DEP mainly involving Ca 2+ regulation (N = 11) (e.g. RYR1, calmodulin, calsequestrin, calpain), protein degradation (N = 6), antioxidants (N = 4), plasma membranes (N = 3), glyco(geno)lysis (N = 3) and 21 DEP being blood-borne. ↓DEP (N = 73) were largely mitochondrial (N = 45) impacting the electron transport system (28), enzymes (6), heat shock proteins (4), and contractile proteins (12) including Ca 2+ binding proteins. There were 812 DEG in RER-susceptible versus control involving the electron transfer system, the mitochondrial transcription/translational response and notably the pro-apoptotic Ca 2+-activated mitochondrial membrane transition pore ( SLC25A27, BAX, ATP5 subunits). Upregulated mitochondrial DEG frequently had downregulation of their encoded DEP with semantic similarities highlighting signaling mechanisms regulating mitochondrial protein translation. RER-susceptible horses treated with dantrolene, which slows sarcoplasmic reticulum Ca 2+ release, showed no DEG compared to control horses. We conclude that RER-susceptibility is associated with alterations in proteins, genes and pathways impacting myoplasmic Ca 2+ regulation, the mitochondrion and protein degradation with opposing effects on mitochondrial transcriptional/translational responses and mitochondrial protein content. RER could potentially arise from excessive sarcoplasmic reticulum Ca 2+ release and subsequent mitochondrial buffering of excessive myoplasmic Ca 2+.

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          The Sequence Alignment/Map format and SAMtools

          Summary: The Sequence Alignment/Map (SAM) format is a generic alignment format for storing read alignments against reference sequences, supporting short and long reads (up to 128 Mbp) produced by different sequencing platforms. It is flexible in style, compact in size, efficient in random access and is the format in which alignments from the 1000 Genomes Project are released. SAMtools implements various utilities for post-processing alignments in the SAM format, such as indexing, variant caller and alignment viewer, and thus provides universal tools for processing read alignments. Availability: http://samtools.sourceforge.net Contact: rd@sanger.ac.uk
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            clusterProfiler: an R package for comparing biological themes among gene clusters.

            Increasing quantitative data generated from transcriptomics and proteomics require integrative strategies for analysis. Here, we present an R package, clusterProfiler that automates the process of biological-term classification and the enrichment analysis of gene clusters. The analysis module and visualization module were combined into a reusable workflow. Currently, clusterProfiler supports three species, including humans, mice, and yeast. Methods provided in this package can be easily extended to other species and ontologies. The clusterProfiler package is released under Artistic-2.0 License within Bioconductor project. The source code and vignette are freely available at http://bioconductor.org/packages/release/bioc/html/clusterProfiler.html.
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              edgeR: a Bioconductor package for differential expression analysis of digital gene expression data

              Summary: It is expected that emerging digital gene expression (DGE) technologies will overtake microarray technologies in the near future for many functional genomics applications. One of the fundamental data analysis tasks, especially for gene expression studies, involves determining whether there is evidence that counts for a transcript or exon are significantly different across experimental conditions. edgeR is a Bioconductor software package for examining differential expression of replicated count data. An overdispersed Poisson model is used to account for both biological and technical variability. Empirical Bayes methods are used to moderate the degree of overdispersion across transcripts, improving the reliability of inference. The methodology can be used even with the most minimal levels of replication, provided at least one phenotype or experimental condition is replicated. The software may have other applications beyond sequencing data, such as proteome peptide count data. Availability: The package is freely available under the LGPL licence from the Bioconductor web site (http://bioconductor.org). Contact: mrobinson@wehi.edu.au
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                Author and article information

                Contributors
                Role: Formal analysisRole: InvestigationRole: Writing – original draftRole: Writing – review & editing
                Role: Data curationRole: Formal analysisRole: MethodologyRole: Writing – review & editing
                Role: ConceptualizationRole: InvestigationRole: Writing – review & editing
                Role: Formal analysisRole: MethodologyRole: Writing – review & editing
                Role: ConceptualizationRole: InvestigationRole: Project administrationRole: ResourcesRole: Writing – review & editing
                Role: Editor
                Journal
                PLoS One
                PLoS One
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                10 February 2021
                2021
                : 16
                : 2
                : e0244556
                Affiliations
                [1 ] Mary Anne McPhail Equine Performance Center, Large Animal Clinical Sciences, College of Veterinary Medicine, Michigan State University, East Lansing, MI, United States of America
                [2 ] Equine Integrated Medicine, PLC, Lexington, KY, United States of America
                Cinvestav-IPN, MEXICO
                Author notes

                Competing Interests: One of the authors (CF) is a practicing veterinarian and owner of the business Equine Integrated Medicine PLC. There are no other relevant declarations relating to employment, consultancy, patents, products in development, or marketed products. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

                Author information
                https://orcid.org/0000-0001-5978-7010
                Article
                PONE-D-20-29481
                10.1371/journal.pone.0244556
                7875397
                33566847
                c0c23e7d-5560-4ea0-b271-7f76bb5357cd
                © 2021 Aldrich et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 22 September 2020
                : 13 December 2020
                Page count
                Figures: 6, Tables: 4, Pages: 24
                Funding
                Funded by: funder-id http://dx.doi.org/10.13039/100001655, Grayson-Jockey Club Research Foundation;
                Award Recipient :
                Funded by: Mary Anne McPhail Endowment
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/100000002, National Institutes of Health;
                Award ID: T32 OD011167
                Award Recipient :
                Research was supported by the Grayson Jockey Club Research Foundation (SJV), the Mary Anne McPhail Endowment at Michigan State University (SJV) and in part by NIH Grant T32 OD011167 to Michigan State University (KJA). The Grayson Jockey Club Research Foundation provided funds to perform the research study and partial salary for one author (DVI). CF is the owner of Equine Integrated Medicine PLC. and identified horses in her practice that were healthy controls or susceptible to RER and facilitated biopsy samples that were obtained by another author (SJV). CF did not receive any financial remuneration for participating in the study. The specific role of these authors is articulated in the 'author contributions' section. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology and Life Sciences
                Organisms
                Eukaryota
                Animals
                Vertebrates
                Amniotes
                Mammals
                Equines
                Horses
                Biology and Life Sciences
                Zoology
                Animals
                Vertebrates
                Amniotes
                Mammals
                Equines
                Horses
                Biology and Life Sciences
                Biochemistry
                Bioenergetics
                Energy-Producing Organelles
                Mitochondria
                Biology and Life Sciences
                Cell Biology
                Cellular Structures and Organelles
                Energy-Producing Organelles
                Mitochondria
                Biology and Life Sciences
                Cell Biology
                Cellular Structures and Organelles
                Cell Membranes
                Membrane Proteins
                Biology and Life Sciences
                Computational Biology
                Genome Analysis
                Gene Ontologies
                Biology and Life Sciences
                Genetics
                Genomics
                Genome Analysis
                Gene Ontologies
                Biology and Life Sciences
                Genetics
                Gene Expression
                Biology and Life Sciences
                Biochemistry
                Proteins
                Muscle Proteins
                Biology and Life Sciences
                Molecular Biology
                Molecular Biology Techniques
                Molecular Biology Assays and Analysis Techniques
                Gene Expression and Vector Techniques
                Protein Expression
                Research and Analysis Methods
                Molecular Biology Techniques
                Molecular Biology Assays and Analysis Techniques
                Gene Expression and Vector Techniques
                Protein Expression
                Biology and Life Sciences
                Cell Biology
                Cellular Structures and Organelles
                Endoplasmic Reticulum
                Sarcoplasmic Reticula
                Biology and Life Sciences
                Cell Biology
                Cell Processes
                Secretory Pathway
                Endoplasmic Reticulum
                Sarcoplasmic Reticula
                Custom metadata
                RNA sequence files have been deposited in the NCBI Sequence Read Archive (BioProject PRJNA641844, accession numbers SRR10997329 – SRR10997344). Mass spectrometry proteomic data are available via the ProteomeXchange Consortium PRIDE repository ( http://www.ebi.ac.uk/pride/archive/projects/PXD020100).

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